The need for a Technetium-99m radiopharmaceutical with biological properties equivalent to or surpassing Iodine-131-o-orthoiodohippurate (OIH) is clearly recognized. The primary goal of this proposal is to characterize and validate such an agent so that it can become available for widespread clinical use. We have shown that Tc-99m N,N'-bis(mercaptoacetyl)ethylenediamine (Tc-99m DADS), and its carboxylate derivative (Tc-99m-CO2-DADS) are rapidly secreted by the renal tubules without renal retention. The exoisomer of Tc-99m-CO2-DADS is comparable to OIH but its potential clinical utility is limited because preparative high pressure liquid chromatography (HPLC) is required to separate it from the endoisomer. We have subsequently developed two new very promising renal agents. Tc-99m hydroxymethylene DADS (Tc-99m HODADS) has two isomeric peaks both comparable to OIH; Tc-99m mercaptoacetyltriglycine (Tc-99m MAG3) is a non isomeric compound producing a single HPLC peak that is also comparable to OIH. The biodistribution and excretion of Tc-99m HODADS, Tc-99m MAG3 and other promising analogs, such as Tc-99m AlphaSCO2DADS, will be compared to OIH and I-125 iothalamate in rats to determine the effect of acid-base balance, dehydration, diuresis, tubular blockade, and unilateral segmental renal artery ligation. These complexes and reference agents will also be studied in clinical disease models including renal ischemia, microembolization, acute obstruction, segmental infarction, aminoglycoside toxicity, postobstructive atrophy and renal artery stenosis. Finally, clinical studies will be conducted in normal volunteers and patients. A Tc-99m replacement for OIH will elimninate the need for most dual isotope renal studies (OIH and Tc-99m DTPA). It will result in improved diagnostic images, more accurate quantitative measurements and a lower cost to the patient. Its rapid renal excretion will result in a lower patient radiation dose and it will probably become the Tc-99m agent of choice for first transit nuclear cardiology studies particularly in pediatric patients. The nearly exclusive tubular clearance may allow earlier detection of tubular dysfunction especially in patients with renal transplants, ischemia, or drug induced nephrotoxicity. Finally, these investigations will lead to an improved understanding of the structure-biodistribution relationships of technetium and transition metal complexes in renal tubular secretion and this understanding may lead to further developments in the field of technetium radiopharmaceutical development.